Project Abstract Significance: Neurodegenerative and malignant diseases along with injury of the central nervous system (CNS) affect millions of Americans. These injuries and diseases are often devastating and difficult to treat, and effective drug delivery remains a significant challenge. Infusion of drugs into the brain parenchyma using convection-enhanced delivery (CED) allows direct treatment of lesions, circumventing the blood brain barrier. In particular, new treatments and diseases call for large regions of brain to be subjected to therapeutic doses. Multiple clinical trials have been conducted using CED to deliver large volumes of chemotherapy and immunotoxins in patients with gliomas, but actual drug delivery to the tumor has been poor for several reasons including the unpredictable dispersion of the drug in the tissue. These adverse events result in reduced efficacy and increased toxicity. To overcome the limitations associated with conventional CED catheters in heterogeneous tissue, the Applicants have developed a Porous Brain Infusion Catheter (PBIC) for improved CNS drug delivery. Hypothesis: The Applicant proposes that Phase II research will create a multi-capability PBIC optimized for small to large volume distribution and short to long durations for multiple (small to large) neurological therapeutics. Phase I Results: Applicant has developed a PBIC that met Aim 1 design requirements as demonstrated in Aim 3 design verification testing that has been passed. In Aim 2 in vivo porcine testing, the PBIC demonstrated superior large volume distribution (p=.03) compared to a standard end port brain infusion catheter, such that the PBIC is expected to be used in brain tumor human studies by a leading brain tumor center. Specific Aims: With the proposed Phase II PBIC research, the Applicants expect to verify and validate an optimized PBIC design that provides broad CED performance capabilities to CNS, including chronic delivery to enhance commercialization potential. Aim 1: The PBIC design will be optimized for small to large volume distribution for multiple therapeutics and short to long durations. The resulting PBIC design verification and performance characterization testing, in vitro and in vivo, will be completed to allow for human use and product approvals. Aim 2: The PBIC design will be validated for human use with therapeutics in non-clinical models, including chronic delivery with the infusion of a chemotherapeutic in companion dog brain tumor patients, demonstrating the IND enabling capabilities of the PBIC for a broad range of therapeutic administration protocols. These Aim 2 studies will reduce PBIC clinical risk and are expected to accelerate customer human study adoption.